The long-term objective of this proposal is to discover and develop an entirely new class of anticancer drugs that: 1) has a novel mechanism of action, 2) is more specific and less toxic than traditional drugs, and 3) has the potential to treat a wide variety of cancers. We will assess the validity and feasibility of using the enzyme telomerase as an innovative target to develop a mechanism-of-action-based drug discovery effort. The concept that telomerase is unique and essential for immortality in tumor cells was pioneered by heron's scientists and advisors. In normal somatic cells, telomerase is absent and telomeres, the ends of chromosomes, gradually shorten, ultimately causing permanent cell-cycle arrest. Most malignant cells, however, maintain short, stable telomeres through the activation of telomerase, the enzyme which synthesizes telomeric DNA. Thus, we will survey a wide variety of normal and malignant tissues and cell lines for telomere length and expression of telomerase. We will then develop an automated high-throughput screen to identify inhibitors of telomerase from a number of large and structurally diverse compound libraries. Active compounds will be selected for further analysis and ultimately clinical development.